Maleate salts of (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino) quinolin-6-yl)-4-(dimethylamino)but-2-enamide and crystalline forms thereof

Abstract

The present application relates to maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)aniline]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, crystalline forms thereof, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.

The invention claimed is: 
     
       1. A crystalline form of maleate salt of (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide, exhibiting:
 (a) a first X-ray powder diffraction pattern comprising peaks of 2-theta angles of about 8.1, 15.0, 17.6, and 23.6 degrees; or 
 (b) a second X-ray powder diffraction pattern comprising peaks of 2-theta angles of about 15.5, 16.8, 20.9, 24.4, 25.2 and 26.5 degrees. 
 
     
     
       2. The crystalline form of  claim 1 , wherein the first X-ray powder diffraction pattern further comprises peaks of 2-theta angles of about 9.0, 18.5, 22.7, 23.0, and 25.1 degrees. 
     
     
       3. The crystalline form of  claim 1 , wherein the second X-ray powder diffraction pattern further comprises peaks of 2-theta angles of about 8.7, 9.8, 14.3, 17.4, 19.3, 19.8, and 23.8 degrees. 
     
     
       4. The crystalline form of  claim 1 , which is characterized as: an anhydrous form, a monohydrate form, or a mixture of the anhydrous and the monohydrate forms. 
     
     
       5. The crystalline form of  claim 1 , wherein the first X-ray powder diffraction pattern is essentially the same as shown in  FIG. 3 . 
     
     
       6. The crystalline form of  claim 1 , wherein the second X-ray powder diffraction pattern is essentially the same as shown in  FIG. 1 . 
     
     
       7. The crystalline form of  claim 1 , wherein the crystalline form exhibits the second X-ray powder diffraction pattern and a differential scanning calorimetry (DSC) thermogram having two endothermic peaks between 153° C. and 180° C. 
     
     
       8. The crystalline form  claim 1 , wherein the crystalline form exhibits the second X-ray powder diffraction pattern and an infrared spectroscopy (IR) spectra comprising one or more peaks at about 3507.20, 3326.14, 3036.83, 2995.35, 2938.83, 2640.50, 2417.18, 2214.77, 1847.62, 1686.72, 1620.70, 1581.83, 1539.15, 1485.39, 1459.27, 1386.91, 1349.85, 1278.17, 1226.56, 1163.32, 1113.32, 1078.80, 1034.16, 979.59, 866.53, 829.88, 747.82, 700.14, 662.23, 556.48, and 487.55 cm −1 . 
     
     
       9. A method for preparing the crystalline form of  claim 1 , comprising: mixing ((E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl) amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide and maleic acid in a water-alcohol solution or an alcohol solution at an elevated temperature. 
     
     
       10. The method of  claim 9 , further comprising: cooling said water-alcohol solution or said alcohol solution to precipitate said crystalline form; and filtering said water-alcohol solution or said alcohol solution after cooling to obtain crystalline (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide maleate. 
     
     
       11. A pharmaceutical composition comprising the crystalline form of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       12. A method for treating or inhibiting cancer comprising, administering to a subject a therapeutically-effective amount of the crystalline form of  claim 1 . 
     
     
       13. The method according to  claim 12 , wherein said cancer is selected from at least one of: breast cancer, ovarian cancer, epidermoid tumors, colon cancer, prostate cancer, kidney cancer, bladder cancer, larynx cancer, esophagus cancer, stomach cancer, lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. 
     
     
       14. The crystalline form of  claim 7 , wherein the differential scanning calorimetry (DSC) thermogram of the crystalline form is substantially as shown in  FIG. 2 . 
     
     
       15. The pharmaceutical composition of  claim 11 , wherein the crystalline form is characterized as: an anhydrous form, a monohydrate form, or a mixture of the anhydrous and the monohydrate forms. 
     
     
       16. The method of  claim 9 , wherein the water-alcohol solution is a water and n-propanol solution, and wherein the alcohol solution is an ethanol solution. 
     
     
       17. The method of  claim 16 , wherein the elevated temperature is about 70° C. 
     
     
       18. A process for preparing the crystalline form of  claim 1 , comprising:
 (a) dissolving (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamid and maleic acid in a water-alcohol solution at a first elevated temperature; 
 (b) filtering, at a second elevated temperature, the water-alcohol solution obtained in (a) to provide a filtrate; 
 (c) cooling the filtrate obtained in (b) to a third elevated temperature; and 
 (d) further cooling the filtrate to about 25° C. and isolating the crystalline form of  claim 1 . 
 
     
     
       19. The process of  claim 18 , wherein the first elevated temperature is from 50° C. to 60° C.; the second elevated temperature is from 45° C. to 55° C.; and the third elevated temperature is about 40° C. 
     
     
       20. The process of  claim 18 , wherein the crystalline form of  claim 1  exhibits the second X-ray powder diffraction pattern.